The HIV-1 Nef protein has a crucial role in viral pathogenicity. Activation of p21-activated kinase 2, Pak2, is one of the functions of Nef relevant to viral pathogenesis. Previous studies have demonstrated that Nef binds Pak2 and induces activation of the kinase in a variety of cell types. Considerable evidence indicates that Pak2 activation by GTP-bound Cdc42 or Racl stimulates T-cell signaling and cellular activation. It is my hypothesis that Nef-mediated activation of Pak2 culminates in similar cellular changes, and that these effects of Nef are essential for HIV-1 pathogenesis. In this research-training proposal, I describe experiments aimed at elucidation of the mechanism of Nef-mediated Pak2 activation. These experiments in turn will help reveal the functional consequences of this activation and its role in viral pathogenesis. It is my expectation that results from these studies may provide novel targets for drug design.